In this paper, we present a computational reverse-engineering analysis for scattering experiments (CREASE) based on genetic algorithms and molecular simulation to analyze the structure within ...self-assembled amphiphilic polymer solutions. For a given input comprised of scattering intensity profiles and information about the amphiphilic polymers in solution, CREASE outputs the structure of the self-assembled micelles (e.g., core and corona diameters, aggregation number) as well as the conformations of the amphiphilic polymer chains in the micelle (e.g., blocks’ radii of gyration, chain radii of gyration, monomer concentration profiles). First, we demonstrate CREASE’s ability to reverse-engineer self-assembled nanostructures for scattering profiles obtained from molecular simulations (or in silico experiments) of generic coarse-grained bead–spring polymer chains in an implicit solvent. We then present CREASE’s outputs for scattering profiles obtained from small-angle neutron scattering (SANS) experiments of poly(d-glucose carbonate) block copolymers in solution that exhibit assembly into spherical nanoparticles. The success of this method is demonstrated by its ability to replicate, quantitatively, the results from in silico experiments and by the agreement in micelle core and corona sizes obtained from microscopy of the in vitro solutions. The primary strength of CREASE is its ability to analyze scattering profiles without an off-the-shelf scattering model and the ability to provide chain and monomer level structural information that is otherwise difficult to obtain from scattering and microscopy alone.
Deep brain stimulation (DBS) has shown remarkable success treating neurological and psychiatric disorders including Parkinson's disease, essential tremor, dystonia, epilepsy, and obsessive-compulsive ...disorder. DBS is now being explored to improve cognitive and functional outcomes in other psychiatric conditions, such as those characterized by reduced N-methyl-D-aspartate (NMDA) function (i.e., schizophrenia). While DBS for movement disorders generally involves high-frequency (>100 Hz) stimulation, there is evidence that low-frequency stimulation may have beneficial and persisting effects when applied to cognitive brain networks.
In this study, we utilize a novel technology, functional ultrasound imaging (fUSI), to characterize the cerebrovascular impact of medial septal nucleus (MSN) DBS under conditions of NMDA antagonism (pharmacologically using Dizocilpine MK-801) in anesthetized male mice.
Imaging from a sagittal plane across a variety of brain regions within and outside of the septohippocampal circuit, we find that MSN theta-frequency (7.7 Hz) DBS increases hippocampal cerebral blood volume (CBV) during and after stimulation. This effect was not present using standard high-frequency stimulation parameters i.e., gamma (100 Hz).
These results indicate the MSN DBS increases circuit-specific hippocampal neurovascular activity in a frequency-dependent manner and does so in a way that continues beyond the period of electrical stimulation.
There is significant evidence for cognitive decline following deep brain stimulation (DBS). Current stimulation paradigms utilize gamma frequency stimulation for optimal motor benefits; however, ...little has been done to optimize stimulation parameters for cognition. Recent evidence implicates subthalamic nucleus (STN) theta oscillations in executive function, and theta oscillations are well-known to relate to episodic memory, suggesting that theta frequency stimulation could potentially improve cognition in Parkinson’s disease (PD).
To evaluate the acute effects of theta frequency bilateral STN stimulation on executive function in PD versus gamma frequency and off, as well as investigate the differential effects on episodic versus nonepisodic verbal fluency.
Twelve patients (all males, mean age 60.8) with bilateral STN DBS for PD underwent a double-blinded, randomized cognitive testing during stimulation at (1) 130–135 Hz (gamma), (2) 10 Hz (theta) and (3) off. Executive functions and processing speed were evaluated using verbal fluency tasks (letter, episodic category, nonepisodic category, and category switching), color-word interference task, and random number generation task. Performance at each stimulation frequency was compared within subjects.
Theta frequency significantly improved episodic category fluency compared to gamma, but not compared to off. There were no significant differences between stimulation frequencies in other tests.
In this pilot trial, our results corroborate the role of theta oscillations in episodic retrieval, although it is unclear whether this reflects direct modulation of the medial temporal lobe and whether similar effects can be found with more canonical memory paradigms. Further work is necessary to corroborate our findings and investigate the possibility of interleaving theta and gamma frequency stimulation for concomitant motor and cognitive effects.
•Cognition was assessed in patients with STN DBS for PD.•Low frequency stimulation improves episodic verbal fluency vs baseline high frequency.•No effect was seen in nonepisodic verbal fluency or other executive functions.•There were no differences between high frequency stimulation and no stimulation.•These results corroborate a role of theta oscillations in episodic memory.
The pathophysiologic mechanisms underpinning idiopathic normal pressure hydrocephalus (iNPH), a clinically diagnosed dementia-causing disorder, continue to be explored. An increasing body of evidence ...implicates multiple systems in the pathogenesis of this condition, though a unifying causative etiology remains elusive. Increased knowledge of the aberrations involved has shed light on the iNPH phenotype and has helped to guide prognostication for treatment with cerebrospinal fluid diversion. In this review, we highlight the central role of the cerebrovasculature in pathogenesis, from hydrocephalus formation to cerebral blood flow derangements, blood-brain barrier breakdown, and glymphatic pathway dysfunction. We offer potential avenues for increasing our understanding of how this disease occurs.
Treatments for Alzheimer's disease are urgently needed given its enormous human and economic costs and disappointing results of clinical trials targeting the primary amyloid and tau pathology. On the ...other hand, deep brain stimulation (DBS) has demonstrated success in other neurological and psychiatric disorders leading to great interest in DBS as a treatment for Alzheimer's disease.
We review the literature on 1) circuit dysfunction in Alzheimer's disease and 2) DBS for Alzheimer's disease. Human and animal studies are reviewed individually.
There is accumulating evidence of neural circuit dysfunction at the structural, functional, electrophysiological, and neurotransmitter level. Recent evidence from humans and animals indicate that DBS has the potential to restore circuit dysfunction in Alzheimer's disease, similarly to other movement and psychiatric disorders, and may even slow or reverse the underlying disease pathophysiology.
DBS is an intriguing potential treatment for Alzheimer's disease, targeting circuit dysfunction as a novel therapeutic target. However, further exploration of the basic disease pathology and underlying mechanisms of DBS is necessary to better understand how circuit dysfunction can be restored. Additionally, robust clinical data in the form of ongoing phase III clinical trials are needed to validate the efficacy of DBS as a viable treatment.
Cortical oscillations within or across brain regions play fundamental roles in sensory, motor, and memory functions. It can be altered by neuromodulations such as repetitive transcranial magnetic ...stimulation (rTMS) and pharmacological manipulations such as ketamine. However, the neurobiological basis of the effects of rTMS and ketamine, as well as their interactions, on cortical oscillations is not understood. In this study, we developed and applied a rodent model that enabled simultaneous rTMS treatment, pharmacological manipulations, and invasive electrophysiological recordings, which is difficult in humans. Specifically, a miniaturized C-shaped coil was designed and fabricated to deliver focal subthreshold rTMS above the primary somatosensory (S1) and motor (M1) cortex in rats. Multi-electrode arrays (MEA) were implanted to record local field potentials (LFPs) and single unit activities. A novel form of synchronized activities, poly population spikes (PPS), was discovered as the biomarker of ketamine in LFPs. Brief subthreshold rTMS effectively and reversibly suppressed PPS while increasing the firing rates of single unit activities. These results suggest that ketamine and rTMS have convergent but opposing effects on cortical oscillations and circuits. This highly robust phenomenon has important implications to understanding the neurobiological mechanisms of rTMS and ketamine as well as developing new therapeutic strategies involving both neuromodulation and pharmacological agents.
Early life stress may have profound effects on brain health, yielding both short- and long-term cognitive or psychiatric impairment. Early life Social Instability Stress (SIS) in rodents has been ...used to model the effects of early chronic human stress. While many studies have assessed acute and short-term responses to this stressor, less attention has been paid to the lasting effects of early life stress in rodents.
The current study utilized SIS in young mice to assess the impact of early life adversity over the lifespan. Mice were assessed in adulthood between the ages of 18 to 66 weeks for changes in behaviors associated with anxiety, affect, sociability, aggression, motivation, and recognition memory. Additionally, mice were assessed for changes in glucocorticoid level and hippocampal mRNA expression in a subset of genes that display alterations in humans following exposure to stress (CRHR1, CRHR2, FKBP5, SLC6A4).
Mice exposed to early SIS showed disrupted memory and increased hippocampal expression of FKBP5, CRHR2 and SLC6A4 mRNA compared to non-stressed mice. Importantly, there was a significant association between increased FKBP5 and CRHR2 with reduced recognition memory. Additionally, mice exposed to SIS showed increased responding on a progressive ratio schedule of reinforcement, indicating that reduction in memory performance was not mediated by decreased effort.
Ecologically-relevant social stress in mice causes long-term decrements in recognition memory, possibly mediated by persistent changes in moderators of the stress cascade. Additionally, animals exposed to early life stress showed increased motivation for reward, which may contribute to a host of hedonic seeking behaviors throughout life. These data suggest that SIS can be used to evaluate therapeutic interventions to attenuate or reverse lasting effects of early life adversity.
•Social instability stress (SIS) is used to model early life stress in male and female mice.•Adolescent exposure to SIS leads to novel object recognition (NOR) deficits in middle age.•SIS mice showed increased motivation on the progressive ratio task.•Mice exposed to SIS had increased levels of FKBP5 and CRHR2 versus controls at 66 weeks.•NOR performance was significantly correlated with both FKBP5 and CRHR2 expression.
Deep brain stimulation (DBS) is currently used to treat addiction, with the nucleus accumbens (NAc) as one promising target. The anterior limb of the internal capsule (ALIC) is also a potential ...target, as it carries fiber tracts connecting the mesocorticolimbic circuits that are crucially involved in several psychiatric disorders, including addiction. Stimulating the NAc and ALIC simultaneously may have a synergistic effect against addiction.
Eight patients with a long history of heroin use and multiple relapses, despite optimal conventional treatments, were enrolled. Customized electrodes were implanted through the ALIC into the NAc, and deep brain stimulation (DBS) treatment began two weeks after surgery. The patients were followed for at least 24 months. The duration of drug-free time, severity of drug cravings, psychometric evaluations, and PET studies of glucose metabolism before and after DBS were conducted. All adverse events were recorded.
With DBS, five patients were abstinent for more than three years, two relapsed after abstaining for six months, and one was lost of follow-up at three months. The degree of cravings for drug use after DBS was reduced if the patients remained abstinent (p < 0.001). Simultaneous DBS of the NAc and ALIC also improved the quality of life, alleviated psychiatric symptoms, and increased glucose metabolism in addiction-related brain regions. Moreover, stimulation-related adverse events were few and reversible.
Simultaneous DBS of the NAc and ALIC appears to be safe, with few side effects, and may prevent long-term heroin relapse after detoxification in certain patients. (This trial was registered at ClinicalTrials.gov, NCT01274988).
•Bilateral NAc and ALIC were simultaneously stimulated in heroin addicts for preventing relapse after detoxification.•Five of eight patients have kept abstinent for more than 3 years, with few side effects.•Decreased cravings for drug use, improved quality of life and alleviated mental disorders were observed.•Simultaneous DBS of NAc and ALIC appears to be safe, and produces long-term effects for preventing heroin relapse.
Temporal lobe epilepsy is most prevalent among focal epilepsies, and nearly one-third of patients are refractory to pharmacological intervention. Persistent cognitive and neurobehavioral ...comorbidities also occur due to the recurrent nature of seizures and medication-related side effects.
Electrical neuromodulation is an effective strategy to reduce seizures both in animal models and clinically, but its efficacy to modulate cognition remains unclear. We hypothesized that theta frequency stimulation of the medial septum would increase septohippocampal oscillations, increase seizure threshold, and improve spatial learning in a rat model of pilocarpine-induced epilepsy.
Sham and pilocarpine rats were implanted with electrodes in the medial septum, hippocampus and prefrontal cortex. EEG was assessed days prior to and following stimulation. Sham and pilocarpine-treated rats received either no stimulation, continuous (throughout each behavior), or pre-task (one minute prior to each behavior) 7.7 Hz septal stimulation during the Barnes maze spatial navigation test and also during assessment of flurothyl-induced seizures.
Both continuous and pre-task stimulation prevented epilepsy-associated reductions in theta oscillations over time. Additionally, both stimulation paradigms significantly improved spatial navigation in the Barnes maze, reducing latency and improving search strategy. Moreover, stimulation led to significant increases in seizure threshold in pilocarpine-treated rats. There was no evidence of cognitive enhancement or increased seizure threshold in stimulated sham rats.
These findings have profound implications as theta stimulation of the septum represents a single frequency and target that has the potential to both improve cognition and reduce seizures for patients with refractory epilepsy.
•Stimulation at theta frequency increases seizure threshold in epileptic rats.•Stimulation concurrently improves learning and memory in epileptic rats.•Both continuous and pre-task stimulation result in similar improvements.•Stimulation does not enhance performance in control animals.
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